The identification of rare mutations that result in predisposition to SCZ with relatively high penetrance has led to the development of mouse models of proven etiologic relevance. DISC1 is a susceptibility gene identified through a rare genetic lesion, a balanced chromosomal translocation segregating with SCZ and mood disorders in a large pedigree. We used a disease-focused knock-in approach to introduce a truncating lesion in the murine Disc1 orthologue designed to model the effects of this translocation. During the first round of this grant we showed that Disc1 mutant mice display specific and robust deficiencies in spatial working memory tests. We also uncovered widespread cytoarchitectural alterations in the dentate gyrus during neonatal and adult neurogenesis, which include errors in axonal pathfinding and are accompanied by changes in neural activity and short-term plasticity. We also showed that dysregulation of cAMP levels contributes to the structural connectivity deficits. Finally we provided evidence that mutant mice have altered functional connectivity of prefrontal areas with temporal lobe structures. Building on these findings, here we propose to complete our analysis on the effect of the Disc1 mutation on hippocampus, extend our structural and functional analysis to prefrontal cortex and finally analyze the effect of the modeled mutation on the communication between these two areas. In addition to our previous results from Disc1 mutant mice our proposed research is dictated by parallel analysis of other models of rare mutations, which affords the opportunity to compare results, identify key common pathways and enable development of a comprehensive and integrative model of schizophrenia pathogenesis and pathophysiology. This knowledge will facilitate discovery of novel treatments and biomarkers. PUBLIC HEALTH RELEVANCE: Schizophrenia is a common and complex psychiatric disorder with a strong genetic component. This proposal is inherently translational in nature, aimed at identifying specific patterns of abnormal brain structure and function caused by schizophrenia predisposing genes. Identifying such patterns would facilitate novel approaches to therapies aimed at reversing the underlying pathophysiology and restoring normal function.